LETTERS

References 1. World Health Organization. Eighth Meeting of the WHO Advisory Sustained Elevated Cytokine Group on the EVD Response; 2015 Mar 20; Geneva. Geneva: Levels during Recovery Phase The Organization; 2015 [cited 2015 Mar 25]. http://www.who.int/ csr/disease/ebola/advisory-groups/8th-meeting-report.pdf?ua=1 of Mayaro Infection 2. World Health Organization. WHO Statement on the Meeting of the International Health Regulations Emergency Committee Regarding the 2014 Ebola Outbreak in West Africa; 2014 Aug Dennis Tappe, José Vicente Pérez-Girón, 8; Geneva. Geneva: The Organization; 2014 [cited 2014 Nov 3]. Gudrun Just-Nübling, Gernot Schuster, http://www.who.int/mediacentre/news/statements/2014/ ebola-20140808/en/ Sergio Gómez-Medina, Stephan Günther, 3. Osterholm MT, Moore KA, Kelley NS, Brosseau LM, Wong G, César Muñoz-Fontela, Jonas Schmidt-Chanasit Murphy FA, et al. Transmission of Ebola : what we know Author affiliations: Bernhard Nocht Institute for Tropical Medicine, and what we do not know. mBiol. 2015;6 [cited 2016 Jan 19]. http://dx.doi: 10.1128/mBio.00137-15 Hamburg, Germany (D. Tappe, S. Günther, C. Muñoz-Fontela, 4. Bausch DG, Towner JS, Dowell SF, Kaducu F, Lukwiya M, J. Schmidt-Chanasit); German Centre for Infection Research, Sanchez A, et al. Assessment of the risk of Ebola virus Hamburg (D. Tappe, S. Günther, C. Muñoz-Fontela, transmission from bodily fluids and fomites. J Infect Dis. J. Schmidt-Chanasit); Leibniz Institute for Experimental Virology, 2007;196(Suppl 2):S142–7. http://dx.doi.org/10.1086/520545 5. Rodriguez LL, De Roo A, Guimard Y, Trappier SG, Sanchez A, Hamburg (J. Vicente Pérez-Girón, S. Gómez-Medina, Bressler D, et al. Persistence and genetic stability of Ebola virus C. Muñoz-Fontela); J.W. Goethe University Center for Infectious during the outbreak in Kikwit, Democratic Republic of the Congo, and Tropical Diseases, Frankfurt, Germany (G. Just-Nübling); 1995. J Infect Dis. 1999;179(Suppl 1):S170–6. http://dx.doi.org/ Praxis Schuster, Reinhardshagen, Germany (G. Schuster) 10.1086/514291 6. ProMEDmail. Ebola virus disease—ex Africa (39): India, DOI: http://dx.doi.org/10.3201/eid2204.151502 worldwide susp. or quarantined. 2014 Nov 18 [cited 2015 Dec 23]. http://www.promedmail.org, archive no. 20141118.2966874. To the Editor: Mayaro virus (MAYV), a - 7. Towner JS, Sealy TK, Ksiazek TG, Nichol ST. High-throughput borne to , causes a self- molecular detection of hemorrhagic fever virus threats with applications for outbreak settings. J Infect Dis. 2007;196(Suppl limiting febrile arthralgia syndrome closely resembling 2):S205–12. http://dx.doi.org/10.1086/520601 fever (1). MAYV has been detected increas- 8. Ksiazek TG, Rollin PE, Williams AJ, Bressler DS, Martin ML, ingly as imported infections in international travelers re- Swanepoel M, et al. Clinical virology of Ebola hemorrhagic fever turning to Europe and North America (2–9). Joint pain, (EHF): virus, virus antigen, and IgG and IgM antibody findings among EHF patients in Kikwit, Democratic Republic of the Congo, the most prominent symptom, is often long-lasting (sev- 1995. J Infect Dis. 1999;179(Suppl 1):S177–87. http://dx.doi.org/ eral months), sometimes incapacitating (4,6,7,9), and may 10.1086/514321 recur (8). Arthralgia develops during the acute phase and 9. Drosten C, Göttig S, Schilling S, Asper M, Panning M, symmetrically affects the wrists, ankles, and small joints Schmitz H, et al. Rapid detection and quantification of RNA of Ebola and Marburg viruses, Lassa virus, Crimean-Congo of hands and feet. Joint swelling may occur initially, but hemorrhagic fever virus, virus, , permanent joint damage has not been described (5). The and virus by real-time reverse transcription-PCR. clinical disease and diagnostic procedures have been de- J Clin Microbiol. 2002;40:2323–30. http://dx.doi.org/10.1128/ scribed (1–9), but immunologic parameters and their pos- JCM.40.7.2323-2330.2002 10. O’Dempsey T, Khan SH, Bausch DG. Rethinking the discharge sible role in the clinical follow-up of patients (i.e., during policy for Ebola convalescents in an accelerating epidemic. the postacute long-lasting arthralgia period) remain to Am J Trop Med Hyg. 2015;92:238–9. http://dx.doi.org/10.4269/ be investigated. ajtmh.14-0719 To further our knowledge of MAYV infection, we ana- 11. Deen GF, Knust B, Broutet N, Sesay FR, Formenty P. Ross C et al. Ebola RNA persistence in semen of Ebola virus disease lyzed cytokine levels in serum samples from 6 travelers to survivors—preliminary report. N Engl J Med. 2015 Oct 14 [cited South America who returned to Europe with Mayaro fever 2015 Oct 20]. http://dx.doi.org/10.1056/NEJMoa1511410 (MF). Two of the cases occurred during 2014; 4 occurred during 2011–2013 (2–5). Address for correspondence: Devendra T. Mourya, National Institute The 6 travelers comprised 2 men and 4 women who of Virology, Pune, 20-A, Dr. Ambedkar Rd, Pune (Maharashtra), Pin were 20–54 (median 36) years of age (online Technical Ap- 411001, India; email: [email protected], [email protected] pendix Table, http://wwwnc.cdc.gov/EID/article/22/4/15- 1502-Techapp1.pdf). The 2 most recent cases occurred in spring 2014 in a 28-year-old female student and a 54-year- old male physician. Serologic testing was performed for both patients at the Bernhard Nocht Institute and confirmed by virus neutralization testing (4). The student had traveled for 3 weeks in Ecuador, visit- ing rainforest villages and hiking in the jungle. During her

750 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 22, No. 4, April 2016 LETTERS stay, she had experienced myalgia of the forearms, arthral- IgM and IgG titers (1:320 and 1:2,560, respectively; cut- gia of fingers and toes, subfebrile but elevated body tem- off for both was <1:20) (3). Acute MF was diagnosed. Two peratures, and maculopapular exanthema. On examination weeks later, follow-up serologic testing showed negative in Germany, the student had no clinical signs of disease, but IgM but unchanged IgG titers. Arthralgia with stiffness she reported arthralgia of the ankles and hands. Laboratory lasted for 6 weeks. test results showed a slightly increased C-reactive protein The physician had traveled for 3 weeks through the level (6.2 mg/L, reference value <5 mg/L); liver and kid- jungle in Bolivia, during which time headache, myalgia, ney values and blood count were within reference ranges. shivers, and fatigue developed, followed by foot arthralgia MAYV indirect immunofluorescence assay showed positive and maculopapular exanthema. On his return to Germany,

Figure. Changes in cytokine and growth factor levels in the acute and recovery phase of Mayaro fever. Box-and-whisker plots show median, upper and lower quartile, minimum, and maximum values. A) During the prolonged recovery phase, serum levels of interleukin (IL) 5–10, IL-13, and IL-17 were significantly elevated compared with levels for healthy controls. IL-10 levels were also significantly increased during the acute phase, as were IL- 12p70 levels. B) Significantly increased serum concentrations of interferon-γ (IFN-γ)–induced protein 10 (IP-10), regulated on activation, normal T cell expressed and secreted (RANTES), macrophage inflammatory proteins (MIP)–1α and –1β, granulocyte- macrophage colony-stimulating factor (GM-CSF), and IFN-γ were detected in the prolonged recovery phase; significant elevations were also seen in the acute phase for RANTES and vascular endothelial growth factor (VEGF). Tumor necrosis factor α (TNF-α) concentrations showed a nonsignificant median decrease during the acute phase, whereas eotaxin levels were significantly decreased at that time. *p<0.05 and **p<0.01, versus values for healthy controls (Kruskal-Wallis test).

Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 22, No. 4, April 2016 751 LETTERS he was seen in an outpatient practice for persisting (2 elevations paralleled those described for Chikungunya vi- months) bilateral foot pain. Laboratory test results showed rus infection (10); these elevated levels may help to eluci- C-reactive protein levels, and liver and kidney function val- date the pathogenesis of MAYV-induced arthralgia. More ues, and full blood count within reference ranges. MAYV immunology data are required to complete this evolving indirect immunofluorescence assay was negative for IgM picture of viral arthralgia syndromes. but positive for IgG (1:20,480). Postacute MAYV infection was diagnosed. Two months later, follow-up serologic test- Acknowledgments ing showed unchanged titers. Arthralgia with pronounced We thank Birgit Hüsing, Corinna Thomé, and Alexander morning stiffness lasted for 6 months. Schlaphof for excellent technical assistance. After obtaining written consent from all patients, we subjected their serum samples to multiplex cytokine se- rum analyses (Bio-Rad Laboratories, Munich, Germany). References 1. Azevedo RS, Silva EV, Carvalho VL, Rodrigues SG, Blood was drawn at different times after symptom onset Nunes-Neto JP, Monteiro H, et al. Mayaro fever virus, Brazilian (15–117 days). Serum samples were classified as acute Amazon. Emerg Infect Dis. 2009;15:1830–2. http://dx.doi.org/ (<30 days after symptom onset, n = 3) or postacute (>30 10.3201/eid1511.090461 days after symptom onset, with arthralgia, n = 8). Twenty 2. Slegers CA, Keuter M, Günther S, Schmidt-Chanasit J, van der Ven AJ, de Mast Q. Persisting arthralgia due to Mayaro serum samples from healthy blood donors were run in par- virus infection in a traveler from : is there a risk for atten- allel. During the acute phase of MF, interleukin (IL) 10, dants to the 2014 FIFA World Cup? J Clin Virol. 2014;60:317–9. IL-12p70, RANTES (regulated on activation, normal T cell http://dx.doi.org/10.1016/j.jcv.2014.04.020 expressed and secreted), and vascular endothelial growth 3. Friedrich-Jänicke B, Emmerich P, Tappe D, Günther S, Cadar D, Schmidt-Chanasit J. Genome analysis of Mayaro virus imported to factor concentrations for patients were significantly el- Germany from French Guiana. Emerg Infect Dis. 2014;20:1255–7. evated compared with those for healthy controls (Figure). http://dx.doi.org/10.3201/eid2007.140043 Furthermore, a significant decrease was noted for eotaxin 4. Theilacker C, Held J, Allering L, Emmerich P, Schmidt-Chanasit J, levels during the acute phase of disease. In the postacute ar- Kern WV, et al. Prolonged polyarthralgia in a German traveller with Mayaro virus infection without inflammatory correlates. thralgic recovery phase, concentrations of IL-5–10, IL-13, BMC Infect Dis. 2013;13:369. http://dx.doi.org/10.1186/ IL-17, IP-10 (interferon-γ–induced protein 10), RANTES, 1471-2334-13-369 macrophage inflammatory proteins 1α and 1β, granulocyte- 5. Neumayr A, Gabriel M, Fritz J, Günther S, Hatz C, macrophage colony-stimulating factor, and interferon-γ Schmidt-Chanasit J, et al. Mayaro virus infection in traveler returning from Amazon Basin, northern . Emerg Infect Dis. were significantly higher than those for healthy controls. 2012;18:695–6. http://dx.doi.org/10.3201/eid1804.111717 TNF-α concentrations showed a nonsignificant median 6. Receveur MC, Grandadam M, Pistone T, Malvy D. Infection with decrease during the acute phase (Figure). No significant Mayaro virus in a French traveller returning from the Amazon changes in either phase were demonstrated for IL-1b, IL- region, Brazil, January, 2010. Euro Surveill. 2010;15:19563. 7. Hassing RJ, Leparc-Goffart I, Blank SN, Thevarayan S, 2, IL-4, basic fibroblast growth factor, granulocyte colony- Tolou H, van Doornum G, et al. Imported Mayaro virus stimulating factor, monocyte chemotactic protein 1, and infection in the Netherlands. J Infect. 2010;61:343–5. platelet-derived growth factor β polypeptide levels (data http://dx.doi.org/10.1016/j.jinf.2010.06.009 not shown). Cytokine levels measured in the acute phase 8. Taylor SF, Patel PR, Herold TJ. Recurrent arthralgias in a patient with previous Mayaro fever infection. South Med J. 2005;98:484– did not differ significantly from those measured in the re- 5. http://dx.doi.org/10.1097/01.SMJ.0000145879.14102.F4 covery phase. 9. Tesh RB, Watts DM, Russell KL, Damodaran C, Calampa C, The most striking clinical feature of MF is long-last- Cabezas C, et al. Mayaro virus disease: an emerging mosquito- ing arthralgia, similar to that seen in chikungunya fever, borne in tropical South America. Clin Infect Dis. 1999;28:67–73. http://dx.doi.org/10.1086/515070 which develops in the acute phase and persists thereafter. 10. Rougeron V, Sam IC, Caron M, Nkoghe D, Leroy E, In the travel-associated cases, arthralgia lasted for 2 to >12 Roques P. Chikungunya, a paradigm of neglected tropical months. In the examined patients, the prolonged arthralgia disease that emerged to be a new health global risk. J Clin Virol. recovery phase was paralleled by significantly increased 2015;64:144–52. http://dx.doi.org/10.1016/j.jcv.2014.08.032 proinflammatory cytokine levels, indicating ongoing in- Address for correspondence: Dennis Tappe, Bernhard Nocht Institute for flammation, probably related to arthritis. Elevated levels Tropical Medicine, Bernhard-Nocht-Str. 74, 20359 Hamburg, Germany; of RANTES and IP-10 suggest T-cell recruitment, possibly email: [email protected] reflecting virus persistence and replication, as described for the related Chikungunya virus (10). Thus, cytokine mea- surements may be helpful for monitoring patient symptoms, especially when signs of arthritis (swellings and redness) and elevated standard serum inflammatory parameters are no longer present. In our study, the picture of MF cytokine

752 Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 22, No. 4, April 2016

Article DOI: http://dx.doi.org/10.3201/eid2204.151502 Sustained Elevated Cytokine Levels during Recovery Phase of Mayaro Virus Infection

Technical Appendix

Technical Appendix Table. International travelers recently diagnosed with Mayaro fever included in the study. Cytokine Country level testing, Case Year of of Age, Laboratory days after No. Infection Infection Imported to Sex y Risk Activity (Locality) diagnosis Reference disease onset 1 2014 Ecuador Germany F 28 Jungle Trekking (Macas, Serology This report 26 and 45 Puyo, Tena villages) 2 2014 Germany M 54 Jungle Trekking (Buenavista Serology This report 74, 88, and village) 117 3 2013 Brazil The F 52 Research in the Rainforest Serology (1) 15 Netherlands (Caxiuana village) 4 2013 French Germany F 44 Butterfly Hunting (St. Laurent, PCR and (2) 16 and 33 Guiana Cayenne, Cacao Cities) Serology 5 2012 Bolivia Germany F 20 Work in Wildlife Resort Serology (3) 83 and 106 (Rurrenabaque Region) 6 2011 Peru Switzerland M 27 Vacation in Small Rainforest Serology (4) 44 City (Tarapoto village)

References

1. Slegers CA, Keuter M, Günther S, Schmidt-Chanasit J, van der Ven AJ, de Mast Q. Persisting arthralgia due to Mayaro virus infection in a traveler from Brazil: is there a risk for attendants to the 2014 FIFA World Cup? J Clin Virol. 2014;60:317–9. PubMed http://dx.doi.org/10.1016/j.jcv.2014.04.020

2. Friedrich-Jänicke B, Emmerich P, Tappe D, Günther S, Cadar D, Schmidt-Chanasit J. Genome analysis of Mayaro virus imported to Germany from French Guiana. Emerg Infect Dis. 2014;20:1255–7. PubMed http://dx.doi.org/10.3201/eid2007.140043

3. Theilacker C, Held J, Allering L, Emmerich P, Schmidt-Chanasit J, Kern WV, et al. Prolonged polyarthralgia in a German traveller with Mayaro virus infection without inflammatory correlates. BMC Infect Dis. 2013;13:369. PubMed http://dx.doi.org/10.1186/1471-2334-13-369

4. Neumayr A, Gabriel M, Fritz J, Günther S, Hatz C, Schmidt-Chanasit J, et al. Mayaro virus infection in traveler returning from Amazon Basin, northern Peru. Emerg Infect Dis. 2012;18:695–6. PubMed http://dx.doi.org/10.3201/eid1804.111717

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